Diphenoxylate / Atropine

Antidiarrheal (opioid agonist) Synthetic opioid (meperidine congener) combined with anticholinergic Rx Controlled Schedule V (in the US, when combined with atropine)

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 0.05-0.1 mg/kg of diphenoxylate (combined with atropine at 0.0005-0.001 mg/kg) q8-12h Duration: Up to 2-3 days; discontinue if diarrhea persists beyond 48 hours
Notes: Use with caution in dogs with hepatic disease, glaucoma, or urinary retention. Not recommended for cats.

Clinical Indications & Species Uses

General Indications
  • Symptomatic relief of acute diarrhea in dogs when infectious causes have been ruled out
Dog (Canine)
  • Symptomatic treatment of acute diarrhea (non-specific, non-infectious)
  • Reduction of fecal output in chronic diarrhea (off-label)

Pharmacology & Mechanism of Action

Drug Class: Antidiarrheal (opioid agonist) | Pharmacological Group: Synthetic opioid (meperidine congener) combined with anticholinergic

Mechanism of Action: Diphenoxylate is a synthetic opioid that acts on μ-opioid receptors in the gastrointestinal tract, reducing intestinal motility and propulsive contractions, thereby prolonging transit time and allowing increased absorption of water and electrolytes. It also decreases intestinal secretion and increases resting tone of the gut. Atropine is added at subtherapeutic doses to discourage deliberate misuse (abuse potential) and to provide anticholinergic effects that may contribute to reducing intestinal secretions and motility.

Pharmacodynamics: Diphenoxylate produces its antidiarrheal effect by slowing intestinal motility and increasing segmentation contractions, which enhances fluid and electrolyte absorption. Atropine, at the low dose present, may cause mild anticholinergic effects such as dry mouth and mydriasis, but its primary purpose is to limit abuse potential. The combination results in a synergistic reduction of diarrhea.

⚡ Pharmacokinetics Summary

Absorption: Diphenoxylate is well absorbed after oral administration, with peak plasma concentrations occurring within 2-3 hours. Atropine is also well absorbed orally.
Distribution: Diphenoxylate is widely distributed in tissues; it crosses the blood-brain barrier to some extent, which may contribute to central effects. Atropine is distributed throughout the body and crosses the placenta and blood-brain barrier.
Metabolism: Diphenoxylate is extensively metabolized in the liver to its active metabolite, difenoxin, which is more potent and has a longer half-life. Atropine is metabolized in the liver via hydrolysis and conjugation.
Excretion: Diphenoxylate and its metabolites are excreted primarily in the feces via bile, with some renal excretion. Atropine is excreted in the urine, with about 30-50% unchanged.
Half-Life: Diphenoxylate: approximately 2.5 hours in dogs; difenoxin: 12-14 hours in dogs. Atropine: 2-3 hours in dogs.
Bioavailability: Oral bioavailability of diphenoxylate is approximately 90% in dogs; atropine has variable oral bioavailability (20-50%) due to first-pass metabolism.
Protein Binding: Diphenoxylate: approximately 80% bound to plasma proteins; difenoxin: 90% bound. Atropine: approximately 44% bound.

Available Formulations & Strengths

Oral Tablet 2.5 mg diphenoxylate / 0.025 mg atropine sulfate per tablet (PO)
Oral Solution 2.5 mg diphenoxylate / 0.025 mg atropine sulfate per 5 mL (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to diphenoxylate or atropine
  • Known infectious diarrhea (e.g., parvovirus, bacterial enteritis) due to risk of prolonged infection
  • Obstructive gastrointestinal disease
  • Glaucoma
  • Myasthenia gravis
  • Severe hepatic insufficiency
  • Use in cats (due to increased sensitivity to anticholinergic effects and potential for severe adverse reactions)
Warnings & Clinical Precautions:
  • Use with caution in animals with renal or hepatic impairment, as drug metabolism may be reduced.
  • May cause constipation or paralytic ileus with prolonged use.
  • Atropine may exacerbate tachycardia, urinary retention, and dry eye conditions.
  • Do not use in animals with known infectious diarrhea, as it may mask symptoms and prolong the disease.
  • Use with caution in debilitated or geriatric animals.
  • Monitor for signs of opioid toxicity (e.g., CNS depression, respiratory depression) especially in small breeds.
  • Not recommended for use in cats due to risk of severe adverse effects.

Adverse Effects & Reactions

Common:

  • Constipation
  • Dry mouth
  • Mydriasis
  • Sedation
  • Decreased appetite

Serious / Severe:

  • Paralytic ileus
  • Respiratory depression
  • CNS depression
  • Severe constipation
  • Urinary retention
  • Hyperthermia (especially in cats)

Rare:

  • Hypersensitivity reactions
  • Pancreatitis
  • Hepatotoxicity

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Other CNS depressants (e.g., barbiturates, benzodiazepines, opioids) Additive CNS and respiratory depression High
MAO inhibitors Increased risk of hypertensive crisis and CNS excitation High
Anticholinergic drugs (e.g., atropine, antihistamines) Additive anticholinergic effects (e.g., dry mouth, urinary retention, tachycardia) Moderate
Drugs that prolong QT interval (e.g., fluoroquinolones, macrolides) Potential additive QT prolongation Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • CNS depression
  • Respiratory depression
  • Coma
  • Mydriasis
  • Tachycardia
  • Hyperthermia
  • Paralytic ileus
  • Urinary retention

Emergency Treatment Protocol: Induce emesis if recent ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Provide supportive care including IV fluids, oxygen therapy, and respiratory support. Naloxone (0.01-0.04 mg/kg IV) can be used to reverse opioid effects, but may need repeated dosing due to diphenoxylate's long half-life. Monitor for atropine toxicity (e.g., hyperthermia, tachycardia) and treat symptomatically (e.g., physostigmine for severe anticholinergic signs).

Food Animal Withdrawal Times

Not approved for use in food animals; no withdrawal times established. Use in food animals is prohibited.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature 20-25°C (68-77°F)

Handling & Special Conditions: Protect from moisture; keep container tightly closed.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Approved for use in humans; not FDA-approved for veterinary use, but may be used off-label in dogs.

Extra-Label (Off-Label) Use: In the US, extra-label use in food animals is prohibited due to lack of established withdrawal times and potential for residues. In dogs, extra-label use is permitted under AMDUCA with appropriate veterinary oversight.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Diphenoxylate/atropine is primarily used in dogs for symptomatic treatment of acute, non-infectious diarrhea. It should not be used in cats due to the risk of severe adverse effects, including hyperthermia and CNS excitation. It is essential to rule out infectious causes of diarrhea before administration, as it can worsen certain infections. The drug is a controlled substance (Schedule V) due to its opioid component, so proper storage and record-keeping are required. Use the lowest effective dose for the shortest duration possible. Monitor for signs of constipation or CNS depression, especially in small or debilitated animals. For chronic diarrhea, alternative therapies should be considered.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)